Novel small molecule inhibition of IKK/NF-κB activation reduces markers of senescence and improves healthspan in mouse models of aging

Lei Zhang, Jing Zhao, Xiaodong Mu, Sara J. McGowan, Luise Angelini, Ryan D. O'Kelly, Matthew J. Yousefzadeh, Ayumi Sakamoto, Zaira Aversa, Nathan K. LeBrasseur, Yousin Suh, Johnny Huard, Theodore M. Kamenecka, Laura J. Niedernhofer, Paul D. Robbins

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

Constitutive NF-κB activation is associated with cellular senescence and stem cell dysfunction and rare variants in NF-κB family members are enriched in centenarians. We recently identified a novel small molecule (SR12343) that inhibits IKK/NF-κB activation by disrupting the association between IKKβ and NEMO. Here we investigated the therapeutic effects of SR12343 on senescence and aging in three different mouse models. SR12343 reduced senescence-associated beta-galactosidase (SA-β-gal) activity in oxidative stress-induced senescent mouse embryonic fibroblasts as well as in etoposide-induced senescent human IMR90 cells. Chronic administration of SR12343 to the Ercc1−/ and Zmpste24−/− mouse models of accelerated aging reduced markers of cellular senescence and SASP and improved multiple parameters of aging. SR12343 also reduced markers of senescence and increased muscle fiber size in 2-year-old WT mice. Taken together, these results demonstrate that IKK/NF-κB signaling pathway represents a promising target for reducing markers of cellular senescence, extending healthspan and treating age-related diseases.

Original languageEnglish (US)
Article numbere13486
Pages (from-to)e13486
JournalAging cell
Volume20
Issue number12
DOIs
StatePublished - Dec 2021

Bibliographical note

Funding Information:
This work was supported by NIH grants RO1 AG063543‐02S1 (LJN, PDR), P01 AG043376 (PDR, LJN, JH), U19 AG056278 (PDR, LJN, YS), RO1 AG063543 (LJN), P01 AG062413 (LJN, PDR, TK, NKL) and the Glenn Foundation (LJN, NKL). MJY is supported by The Irene Diamond Fund/American Federation on Aging Research Postdoctoral Transition Award.

Publisher Copyright:
© 2021 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.

Keywords

  • NEMO
  • NF-κB
  • SR12343
  • aging
  • senescence

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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